Since the cellular and molecular underpinnings of inflammatory arthritides, in particular rheumatoid arthritis, remain enigmatic, significant controversy surrounds the mechanisms responsible for these frequent and debilitating autoimmune disorders. A murine model that has incited much interest of late is K/BxN T cell receptor transgenic mice, which spontaneously develop an inflammatory arthritis with many of the features of rheumatoid arthritis in humans. Disease is provoked by T, then B, cell reactivity to glucose-6-phosphate-isomerase (GPI), and can be induced in healthy recipients by transfer of K/BxN serum (containing anti-GPI antibodies). Serum-transferred disease -- i.e. the end, effector stage -- depends on neutrophils, mast cells, immune complexes, Fc receptors, the alternative pathway of complement, Tumor Necrosis Factor-alpha and lnterleukin-1. This proposed project has as its overall goal the application of novel imaging methodologies developed under Project 1 to a specific set of outstanding issues that have arisen in the context of the K/BxN serum-transfer system. The major aims are to: 1. Image the joint microvasculature during the arthritic process to determine the time-course of vascular alterations at disease onset; assess these changes in relation to the cells and molecules known to impinge on the disease process; and test whether the distribution of joint lesions reflects vascular alterations. 2. Image and track cells to ascertain the origin, timing of recruitment and destination of the various cellular players critical for disease progression. 3. Image protease activity to co-correlate osteoclast activity, inflammatory cell involvement and regenerative osteoblast function; to identify proteases that serve to diagnose, stage or stratify different arthritides; and to explore the activity of serine proteases that participate in the alternative pathway of complement. These studies should generate novel information on arthritogenesis, and may also suggest diagnostic or therapeutic strategies worth exploring in human arthritides. may also suggest